Project Summary Despite intense efforts, the long-term cure rates of children and adults with acute myeloid leukemia are not satisfactory. Resistance to cytotoxic chemotherapy and apoptosis is the dominant cause of treatment failure. The molecular mechanisms responsible for chemotherapy resistance are poorly understood, hindering the development of therapeutic strategies to induce chemosensitivity. We have found that chemotherapy and apoptosis resistance in high-risk AML requires aberrant phosphorylation of MEF2C, a key transcriptional regulator of leukemia cell growth and survival. The central hypothesis of this proposal is that defining the apoptotic mechanisms dysregulated by aberrant MEF2C signaling will reveal effective therapeutic strategies to overcome treatment resistance. The applicant, who is a New Investigator, will test this hypothesis by investigating the molecular mechanisms of apoptosis resistance in primary human and genetically-engineered mouse leukemias. Aim 1 will elucidate both transcriptional and cellular mechanisms of therapy resistance, with the goal of identifying MEF2C targets that are necessary and sufficient for chemoresistance. Aim 2 will pursue the preliminary evidence that MARK family kinases aberrantly phosphorylate MEF2C and devise rational combination strategies to overcome chemotherapy resistance induced by MEF2C phosphorylation. Successful completion of this project is expected to yield molecular mechanisms of aberrant survival and chemotherapy resistance of high-risk AML, thus providing essential insights into a fundamental biological and clinical problem, which can be rapidly translated into clinical trials for patients with this disease.